Synthetic lethal interaction of CDK inhibition and autophagy inhibition in human solid cancer cell lines

Okada,Yoshinari; Kato,Shunsuke; Sakamoto,Yasuhiro; Oishi,Takayuki; Ishioka,Chikashi

doi:10.3892/or.2017.5684

Synthetic lethal interaction of CDK inhibition and autophagy inhibition in human solid cancer cell lines

Authors:
- Yoshinari Okada
- Shunsuke Kato
- Yasuhiro Sakamoto
- Takayuki Oishi
- Chikashi Ishioka
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Affiliations: Department of Clinical Oncology, IDAC, Tohoku University, Aoba-ku, Sendai 980-8575, Japan
Published online on: May 30, 2017 https://doi.org/10.3892/or.2017.5684
Pages: 31-42
Copyright: © Okada et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Cell cycle control is a promising target in cancer treatments, and some small-molecule cyclin-dependent kinase (CDK) inhibitors have exhibited clinical effectiveness. However, no biomarkers predictive of efficacy have been developed. Recent studies have revealed that CDK inhibitor (CKI) proteins, such as p27 and p16, also induced cytoprotective autophagy in cancer cells. However, it is unclear whether small-molecule CKIs also induce autophagy in solid tumors, as induced autophagy promotes cancer cell survival. In this study, we revealed that a CDK4 inhibitor and a CKI with a broad range of targets (flavopiridol) induced autophagy in some, but not all, solid cancer cell lines. Autophagy induction by CDK4 inhibitor was observed in BT474, MDA-MB435S, SKBr3 (derived from breast cancer), A431 (derived from epidermoid cancer), and SW480 (derived from colorectal cancer) cell lines. No such autophagy was observed in MCF7, MDA-MB231 (derived from breast cancer), NCI-N87 (derived from gastric cancer), and KMST-6 (derived from a fibroblast). In the cell lines showing autophagy, which was induced by CDK4 inhibitor, the combination of CDK4 inhibitor and autophagy inhibition by either chloroquine (CQ) or knockdown of ATG5 or BECN1 induced apoptosis. However, it did not induce apoptosis in the cell lines in which autophagy was not induced by CDK4 inhibitor. These findings indicate that the autophagy induced by CDK4 inhibitor mimics stress-induced autophagy in some solid cancer cell lines. The combination of a small-molecule CKI involved in G1/S arrest and an autophagy inhibitor leads to a synthetic lethal interaction and could become a new antitumor strategy for solid tumors showing cytoprotective autophagy induced by small-molecule CKIs.

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